EP4181890B1 - Verwendung von cannabidiol bei der behandlung von mit rett-syndrom assoziierten anfällen - Google Patents

Verwendung von cannabidiol bei der behandlung von mit rett-syndrom assoziierten anfällen

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Publication number
EP4181890B1
EP4181890B1 EP21746419.7A EP21746419A EP4181890B1 EP 4181890 B1 EP4181890 B1 EP 4181890B1 EP 21746419 A EP21746419 A EP 21746419A EP 4181890 B1 EP4181890 B1 EP 4181890B1
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cbd
preparation
seizures
use according
thc
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EP4181890A1 (de
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Daniel Adam CHECKETTS
Kevin James CRAIG
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Jazz Pharmaceuticals Research UK Ltd
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Jazz Pharmaceuticals Research UK Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/658—Medicinal preparations containing organic active ingredients o-phenolic cannabinoids, e.g. cannabidiol, cannabigerolic acid, cannabichromene or tetrahydrocannabinol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/4015—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/423—Oxazoles condensed with carbocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants

Definitions

  • the present invention relates to the use of cannabidiol (CBD) for the treatment of seizures associated with rare epilepsy syndromes.
  • CBD cannabidiol
  • the seizures associated with rare epilepsy syndromes that are treated are those which are experienced in patients diagnosed with Rett syndrome.
  • the types of seizures include tonic, absence seizures and focal seizures with impairment.
  • the dose of CBD is between 5 mg/kg/day to 50 mg/kg/day.
  • the CBD used is in the form of a highly purified extract of cannabis such that the CBD is present at greater than 95% of the total extract (w/w) and the cannabinoid tetrahydrocannabinol (THC) has been substantially removed, to a level of not more than 0.15% (w/w).
  • the CBD used is in the form of a botanically derived purified CBD which comprises greater than or equal to 98% (w/w) CBD and less than or equal to 2% (w/w) of other cannabinoids. More preferably the other cannabinoids present are THC at a concentration of less than or equal to 0.1% (w/w); CBD-C1 at a concentration of less than or equal to 0.15% (w/w); CBDV at a concentration of less than or equal to 0.8% (w/w); and CBD-C4 at a concentration of less than or equal to 0.4% (w/w).
  • the botanically derived purified CBD preferably also comprises a mixture of both trans-THC and cis-THC. Alternatively, a synthetically produced CBD is used.
  • the other cannabinoids present are THC at a concentration of about 0.01% to about 0.1% (w/w); CBD-C1 at a concentration of about 0.1% to about 0.15% (w/w); CBDV at a concentration of about 0.2% to about 0.8% (w/w); and CBD-C4 at a concentration of about 0.3% to about 0.4% (w/w).
  • THC is present at a concentration of about 0.02% to about 0.05% (w/w).
  • the CBD may be formulated for administration separately, sequentially or simultaneously with one or more AED or the combination may be provided in a single dosage form.
  • AED anti-epileptic drugs
  • Epilepsy occurs in approximately 1% of the population worldwide, (Thurman et al., 2011) of which 70% are able to adequately control their symptoms with the available existing anti-epileptic drugs (AED). However, 30% of this patient group, (Eadie et al., 2012), are unable to obtain seizure freedom from the AED that are available and as such are termed as suffering from intractable or "treatment-resistant epilepsy” (TRE).
  • TRE treatment-resistant epilepsy
  • Intractable or treatment-resistant epilepsy was defined in 2009 by the International League against Epilepsy (ILAE) as "failure of adequate trials of two tolerated and appropriately chosen and used AED schedules (whether as monotherapies or in combination) to achieve sustained seizure freedom" (Kwan et al., 2009 ).
  • ILAE International League against Epilepsy
  • Childhood epilepsy is a relatively common neurological disorder in children and young adults with a prevalence of approximately 700 per 100,000. This is twice the number of epileptic adults per population.
  • Childhood epilepsy can be caused by many different syndromes and genetic mutations and as such diagnosis for these children may take some time.
  • the main symptom of epilepsy is repeated seizures.
  • Clinical observations and electroencephalography (EEG) tests are conducted and the type(s) of seizures are classified according to the ILEA classification.
  • Generalized seizures where the seizure arises within and rapidly engages bilaterally distributed networks, can be split into six subtypes: tonic-clonic (grand mal) seizures; absence (petit mal) seizures; clonic seizures; tonic seizures; atonic seizures and myoclonic seizures.
  • Focal (partial) seizures where the seizure originates within networks limited to only one hemisphere, are also split into sub-categories.
  • the seizure is characterized according to one or more features of the seizure, including aura, motor, autonomic and awareness / responsiveness.
  • a seizure begins as a localized seizure and rapidly evolves to be distributed within bilateral networks this seizure is known as a bilateral convulsive seizure, which is the proposed terminology to replace secondary generalized seizures (generalized seizures that have evolved from focal seizures and are no longer remain localized).
  • focal seizures with impairment Focal seizures where the subject's awareness / responsiveness is altered are referred to as focal seizures with impairment and focal seizures where the awareness or responsiveness of the subject is not impaired are referred to as focal seizures without impairment.
  • Rett syndrome is a brain disorder that occurs almost exclusively in girls. After birth, girls with Rett syndrome have 6 to 18 months of apparently normal development before developing severe problems with language and communication, learning, coordination, and other brain functions.
  • MECP2 methyl CpG binding protein 2
  • the MECP2 gene contains instructions for the synthesis of a protein called methyl cytosine binding protein 2 (MeCP2), which is needed for brain development and acts as one of the many biochemical switches that can either increase gene expression or tell other genes when to turn off and stop producing their own unique proteins.
  • MeCP2 methyl cytosine binding protein 2
  • CBD Cannabidiol
  • CBDV cannabidivarin
  • GB 2539472 discloses the use of highly purified CBD for the treatment of various types of seizures. However there is no data shown to suggest efficacy in the treatment of Rett syndrome.
  • An anecdotal report 1 discloses the treatment of a patient diagnosed with Rett syndrome with cannabis oil.
  • the oil used was a full-spectrum cannabis oil, one that retains other compounds such as terpenes and flavonoids. It is further stated that the patient was dosed with a high-THC formulation.
  • the applicant has found by way of an open label, expanded-access program that treatment with CBD resulted in a significant reduction in specific seizure types including tonic, absence seizures and focal seizures with impairment in patients diagnosed with Rett syndrome.
  • CBD cannabidiol
  • the seizures associated with Rett syndrome are tonic, absence seizures and focal seizures with impairment.
  • the CBD preparation comprises greater than 95% (w/w) CBD and not more than 0.15% (w/w) tetrahydrocannabinol (THC).
  • the CBD preparation comprises greater than or equal to 98% (w/w) CBD and less than or equal to 2% (w/w) other cannabinoids, wherein the less than or equal to 2% (w/w) other cannabinoids comprise the cannabinoids tetrahydrocannabinol (THC); cannabidiol-C1 (CBD-C1); cannabidivarin (CBDV); and cannabidiol-C4 (CBD-C4), and wherein the THC is present as a mixture of trans-THC and cis-THC.
  • THC cannabinoids tetrahydrocannabinol
  • CBD-C1 cannabidiol-C1
  • CBDDV cannabidivarin
  • CBD-C4 cannabidiol-C4
  • the CBD preparation is used in combination with one or more concomitant anti-epileptic drugs (AED).
  • AED concomitant anti-epileptic drugs
  • the one or more AED is selected from the group consisting of: clobazam, levetiracetam, zonisamide, valproic acid, perampanel, clonazepam and diazepam.
  • the CBD is present is isolated from cannabis plant material.
  • the CBD is present as a synthetic preparation.
  • the dose of CBD is greater than 5 mg/kg/day. More preferably the dose of CBD is 20 mg/kg/day. More preferably the dose of CBD is 25 mg/kg/day. More preferably the dose of CBD is 50 mg/kg/day.
  • a method of treating seizures associated with Rett syndrome comprising administering a cannabidiol (CBD) preparation to the subject in need thereof.
  • CBD cannabidiol
  • cannabinoids Over 100 different cannabinoids have been identified, see for example, Handbook of Cannabis, Roger Pertwee, Chapter 1, pages 3 to 15 . These cannabinoids can be split into different groups as follows: Phytocannabinoids; Endocannabinoids and Synthetic cannabinoids (which may be novel cannabinoids or synthetically produced phytocannabinoids or endocannabinoids).
  • phytocannabinoids are cannabinoids that originate from nature and can be found in the cannabis plant.
  • the phytocannabinoids can be isolated from plants to produce a highly purified extract or can be reproduced synthetically.
  • “Highly purified cannabinoids” are defined as cannabinoids that have been extracted from the cannabis plant and purified to the extent that other cannabinoids and non-cannabinoid components that are co-extracted with the cannabinoids have been removed, such that the highly purified cannabinoid is greater than or equal to 95% (w/w) pure.
  • Synthetic cannabinoids are compounds that have a cannabinoid or cannabinoid-like structure and are manufactured using chemical means rather than by the plant.
  • Phytocannabinoids can be obtained as either the neutral (decarboxylated form) or the carboxylic acid form depending on the method used to extract the cannabinoids. For example, it is known that heating the carboxylic acid form will cause most of the carboxylic acid form to decarboxylate into the neutral form.
  • Treatment-resistant epilepsy (TRE) or “intractable epilepsy” is defined as per the ILAE guidance of 2009 as epilepsy that is not adequately controlled by trials of one or more AED.
  • Tonic seizures can be generalised onset, affecting both sides of the brain, or they can be focal onset, starting in just one side of the brain. If a tonic seizure starts in both sides of the brain, all muscles tighten and the subject's body goes stiff. If standing, they may fall to the floor, their neck may extend, eyes open wide and roll upwards, whilst their arms may raise upwards and legs stretch or contract. If a tonic seizure starts in one side of the brain muscles tighten in just one area of the body. Tonic seizures usually last less than one minute.
  • Tonic-clonic seizures consist of two phases: the tonic phase and the clonic phase. In the tonic phase the body becomes entire rigid, and in the clonic phase there is uncontrolled jerking. Tonic-clonic seizures may or may not be preceded by an aura, and are often followed by headache, confusion, and sleep. They may last mere seconds or continue for several minutes. These seizures are also known as a grand mal seizure.
  • Absence seizures also may be called “petit mal” seizures. These types of seizure cause a loss of awareness for a short time. They mainly affect children although can happen at any age. During an absence seizure, a person may: stare blankly into space; look like they are “daydreaming”; flutter their eyes; make slight jerking movements of their body or limbs. The seizures usually only last up to 15 seconds and may occur several times a day.
  • “Focal Seizures” are defined as seizures which originate within networks limited to only one hemisphere. What happens during the seizure depends on where in the brain the seizure happens and what that part of the brain normally does.
  • “Focal seizures with impairment” usually start in a small area of the temporal lobe or frontal lobe of the brain and involve other areas of the brain within the same hemisphere that affect alertness and awareness. Most subjects experience automatisms during a focal seizure with impaired consciousness.
  • the drug substance used is a liquid carbon dioxide extract of high-CBD containing chemotypes of Cannabis sativa L. which had been further purified by a solvent crystallization method to yield CBD.
  • the crystallisation process specifically removes other cannabinoids and plant components to yield greater than 95% CBD.
  • CBD is highly purified because it is produced from a cannabis plant rather than synthetically there is a small number of other cannabinoids which are co-produced and co-extracted with the CBD. Details of these cannabinoids and the quantities in which they are present in the medication are as described in Table A below.
  • Table A Composition of highly purified CBD extract Cannabinoid Concentration CBD > 95% w/w CBDA NMT 0.15% w/w CBDV NMT 1.0% w/w ⁇ 9 THC NMT 0.15% w/w CBD-C4 NMT 0.5% w/w > - greater than NMT - not more than
  • the drug substance used in the trials is a liquid carbon dioxide extract of high-CBD containing chemotypes of Cannabis sativa L. which had been further purified by a solvent crystallization method to yield CBD.
  • the crystallisation process specifically removes other cannabinoids and plant components to yield greater than 95% CBD w/w, typically greater than 98% w/w.
  • Cannabis sativa L. plants are grown, harvested, and processed to produce a botanical extract (intermediate) and then purified by crystallization to yield the CBD (botanically derived purified CBD).
  • the plant starting material is referred to as Botanical Raw Material (BRM); the botanical extract is the intermediate; and the active pharmaceutical ingredient (API) is CBD, the drug substance.
  • BRM Botanical Raw Material
  • API active pharmaceutical ingredient
  • Table B CBD botanical raw material specification Test Method Specification Identification: -A Visual Complies -B TLC Corresponds to standard (for CBD & CBDA) -C HPLC/UV Positive for CBDA Assay: CBDA + CBD In-house (HPLC/UV) NLT 90% of assayed cannabinoids by peak area Loss on Drying Ph.Eur. NMT 15% Aflatoxin UKAS method NMT 4ppb Microbial: Ph.Eur.
  • NMT10 7 cfu/g - TVC
  • NMT10 5 cfu/g - Fungi
  • NMT10 2 cfu/g - E.coli Foreign Matter: Ph.Eur.
  • NMT 2% Residual Herbicides and Pesticides Ph.Eur.
  • the purity of the botanically derived purified CBD preparation was greater than or equal to 98%.
  • the botanically derived purified CBD includes THC and other cannabinoids, e.g., CBDA, CBDV, CBD-C1, and CBD-C4.
  • the CBD preparation comprises not more than 0.15% THC based on total amount of cannabinoid in the preparation. In some embodiments, the CBD preparation comprises about 0.01% to about 0.1% THC based on total amount of cannabinoid in the preparation. In some embodiments, the CBD preparation comprises about 0.02% to about 0.05% THC based on total amount of cannabinoid in the preparation.
  • the CBD preparation comprises about 0.2% to about 1.0% CBDV based on total amount of cannabinoid in the preparation. In some embodiments, the CBD preparation comprises about 0.2% to about 0.8% CBDV based on total amount of cannabinoid in the preparation.
  • the CBD preparation comprises about 0.3% to about 0.5% CBD-C4 based on total amount of cannabinoid in the preparation. In some embodiments, the CBD preparation comprises about 0.3% to about 0.4% CBD-C4 based on total amount of cannabinoid in the preparation.
  • the CBD preparation comprises about 0.1% to about 0.15% CBD-C1 based on total amount of cannabinoid in the preparation.
  • Distinct chemotypes of the Cannabis sativa L. plant have been produced to maximize the output of the specific chemical constituents, the cannabinoids. Certain chemovars produce predominantly CBD. Only the (-)-trans isomer of CBD is believed to occur naturally. During purification, the stereochemistry of CBD is not affected.
  • High CBD chemovars were grown, harvested, dried, baled and stored in a dry room until required.
  • the botanical raw material (BRM) was finely chopped using an Apex mill fitted with a 1 mm screen. The milled BRM was stored in a freezer prior to extraction.
  • Decarboxylation of CBDA to CBD was carried out using heat.
  • BRM was decarboxylated at 115°C for 60 minutes.
  • BDS botanical drug substance
  • the BDS produced using the methodology above was dispersed in C 5 -C 12 straight chain or branched alkane.
  • the mixture was manually agitated to break up any lumps and the sealed container then placed in a freezer for approximately 48 hours.
  • the crystals were isolated via vacuum filtration, washed with aliquots of cold C 5 -C 12 straight chain or branched alkane, and dried under a vacuum of ⁇ 10mb at a temperature of 60°C until dry.
  • the botanically derived purified CBD preparation was stored in a freezer at -20°C in a pharmaceutical grade stainless steel container, with FDA food grade approved silicone seal and clamps.
  • the botanically derived purified CBD used in the clinical trial described in the invention comprises greater than or equal to 98% (w/w) CBD and less than or equal to 2% (w/w) of other cannabinoids.
  • the other cannabinoids present are THC at a concentration of less than or equal to 0.1% (w/w); CBD-C1 at a concentration of less than or equal to 0.15% (w/w); CBDV at a concentration of less than or equal to 0.8% (w/w); and CBD-C4 at a concentration of less than or equal to 0.4% (w/w).
  • the botanically derived purified CBD used additionally comprises a mixture of both trans-THC and cis-THC. It was found that the ratio of the trans-THC to cis-THC is altered and can be controlled by the processing and purification process, ranging from 3.3:1 (trans-THC:cis-THC) in its unrefined decarboxylated state to 0.8:1 (trans-THC:cis-THC) when highly purified.
  • the cis-THC found in botanically derived purified CBD is present as a mixture of both the (+)-cis-THC and the (-)-cis-THC isoforms.
  • CBD preparation could be produced synthetically by producing a composition with duplicate components.
  • Example 1 describes the use of a botanically derived purified CBD in an open label, expanded-access program to investigate the clinical efficacy and safety of purified pharmaceutical cannabidiol formulation (CBD) in the treatment of patients diagnosed with Rett syndrome.
  • CBD cannabidiol formulation
  • EXAMPLE 1 CLINICAL EFFICACY AND SAFETY OF PURIFIED PHARMACEUTICAL CANNABIDIOL (CBD) IN THE TREATMENT OF PATIENTS DIAGNOSED WITH RETT SYNDROME
  • Subjects were required to be on one or more AEDs at stable doses for a minimum of two weeks prior to baseline and to have stable vagus nerve stimulation (VNS) settings and ketogenic diet ratios for a minimum of four weeks prior to baseline.
  • VNS vagus nerve stimulation
  • Patients were administered botanically derived purified CBD in a 100 mg/mL sesame oilbased solution which was titrated to an initial dose of between 5 and 25 milligrams per kilogram per day (mg/kg/day) in two divided doses. Doses were then increased weekly by 5mg/kg/day to a goal of 25 mg/kg/day where required.
  • a maximum dose of 50 mg/kg/day could be utilised for patients who were tolerating the medication but had not achieved seizure control; these patients had further weekly titration by 5mg/kg/day.
  • Seizure frequency, intensity, and duration were recorded by caregivers in a diary during a baseline period of at least 28 days. Changes in seizure frequency relative to baseline were calculated after at least 2 weeks and at defined timepoints of treatment.
  • Patients may be defined as responders if they had more than 50% reduction in seizure frequency compared to baseline.
  • the percent change of seizure frequency may be calculated for any time interval where seizure number has been recorded.
  • the three patients enrolled in the open label; expanded-access program were diagnosed with Rett syndrome. These patients experienced a range of different seizure types including tonic, tonic-clonic, absence and focal seizures with impairment.
  • Table 1 Patient demographics, seizure type and concomitant medication
  • Tables 2A-2C illustrate the seizure frequency for each patient as well as the dose of CBD given.
  • Table 2A Seizure frequency data for Patient 1 Patient 1 Time Seizure Type Dose CBD (mg/kg/day) Tonic Tonic-clonic Baseline 22.4 10.0 - 2 weeks 22.0 26.0 5.0 4 weeks 38.0 21.4 10.0 8 weeks 28.0 14.0 20.0 12 weeks 28.0 12.0 25.0 16 weeks 14.0 22.0 15.0 24 weeks 8.0 12.0 15.0 36 weeks 20.0 20.0 15.0
  • Table 2B Seizure frequency data for Patient 2 Patient 2 Time Seizure Type Dose CBD (mg/kg/day) Tonic Absence Focal with impairment Baseline 5.6 0 3.2 - 8 weeks 3.0 1.0 0 20.0 12 weeks 1.6 0 0 20.0 16 weeks 2.0 0 0 20.0 24 weeks 0.4 0.8 0 20.0 36 weeks 0.4 0.4 0 20.0 48 weeks 0.8 0 0 20.0 60 weeks 1.4 0 0 20.0 72 weeks 0.4 0.4 0 21.3 84 weeks 0.4 0.4 0 20.0
  • Table 2C Seizure frequency data for Patient 3
  • Patient 3 Time Seizure Type Dose CBD (mg/kg/day) Tonic Tonic-clonic Absence Baseline 16.0 4.0 8.0 - 4 weeks 2.0 4.0 1.0 25.0 12 weeks 1.0 4.0 0 25.0 16 weeks 4.0 6.0 0 25.0 24 weeks 0 8.0 4.0 25.0 36 weeks 4.0 6.0 1.0 25.0
  • Patient 2 was treated for 36 weeks and experienced a 75% reduction in tonic seizures and an 87.5% reduction in absence seizures over the treatment period.
  • CBD was effective in reducing the frequency of the following seizure types: tonic, absence and focal seizures with impairment. Significantly, one patient became seizure free of focal seizures with impairment (patent 2). All three patients suffered from tonic seizures and all three experienced a reduction in their tonic seizures of between 11-93%.
  • CBD was able to significantly reduce the number of seizures associated with Rett syndrome.
  • the treatment is of significant benefit in this difficult to treat epilepsy syndrome given the high responder rate experienced in all three patients.
  • this study signifies the use of CBD for treatment of seizures associated with Rett syndrome.
  • Seizure types include tonic, absence and focal seizures with impairment for which seizure frequency rates decreased by significant rates, by 11-100.0%.

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Claims (13)

  1. Cannabidiol(CBD-)Präparat zur Verwendung bei der Behandlung von mit Rett-Syndrom assoziierten Anfällen, wobei die mit dem Rett-Syndrom assoziierten Anfälle tonische, Abwesenheits- und fokale Anfälle mit Beeinträchtigung sind.
  2. CBD-Präparat zur Verwendung nach einem der vorhergehenden Ansprüche, wobei das CBD-Präparat mehr als 95 % (w/w) CBD und nicht mehr als 0,15 % (w/w) Tetrahydrocannabinol (THC) umfasst.
  3. CBD-Präparat zur Verwendung nach einem der vorhergehenden Ansprüche, wobei das CBD-Präparat mehr als oder gleich 98 % (w/w) CBD und weniger als oder gleich 2 % (w/w) andere Cannabinoide umfasst, wobei die weniger als oder gleich 2 % (w/w) anderen Cannabinoide die Cannabinoide Tetrahydrocannabinol (THC); Cannabidiol-C1 (CBD-C1); Cannabidivarin (CBDV); und Cannabidiol-C4 (CBD-C4) umfassen, und wobei das THC als ein Gemisch von trans-THC und cis-THC vorhanden ist.
  4. CBD-Präparat zur Verwendung nach einem der vorhergehenden Ansprüche, wobei das CBD-Präparat in Kombination mit einem oder mehreren begleitenden antiepileptischen Arzneimitteln (AED) verwendet wird.
  5. CBD-Präparat zur Verwendung nach Anspruch 4, wobei das eine oder die mehreren AED ausgewählt sind aus der Gruppe bestehend aus: Clobazam, Levetiracetam, Zonisamid, Valproinsäure, Perampanel, Clonazepam und Diazepam.
  6. CBD-Präparat zur Verwendung nach einem der vorhergehenden Ansprüche, wobei das vorliegende CBD aus Cannabispflanzenmaterial isoliert ist.
  7. CBD-Präparat zur Verwendung nach einem der vorhergehenden Ansprüche, wobei mindestens ein Teil von mindestens einem der Cannabinoide, die in der CBD-Präparat vorhanden sind, aus Cannabispflanzenmaterial isoliert ist.
  8. CBD-Präparat zur Verwendung nach Anspruch 1 bis 5, wobei das CBD als eine synthetische Zubereitung vorhanden ist.
  9. CBD-Präparat zur Verwendung nach Anspruch 8, wobei mindestens ein Teil von mindestens einem der Cannabinoide, die in dem CBD-Präparat vorhanden sind, synthetisch zubereitet ist.
  10. CBD-Präparat zur Verwendung nach einem der vorhergehenden Ansprüche, wobei die Dosis von CBD mehr als 5 mg/kg/Tag ist.
  11. CBD-Präparat zur Verwendung nach einem der vorhergehenden Ansprüche, wobei die Dosis von CBD 20 mg/kg/Tag ist.
  12. CBD-Präparat zur Verwendung nach einem der vorhergehenden Ansprüche, wobei die Dosis von CBD 25 mg/kg/Tag ist.
  13. CBD-Präparat zur Verwendung nach einem der vorhergehenden Ansprüche, wobei die Dosis von CBD 50 mg/kg/Tag ist.
EP21746419.7A 2020-07-20 2021-07-15 Verwendung von cannabidiol bei der behandlung von mit rett-syndrom assoziierten anfällen Active EP4181890B1 (de)

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US20230285427A1 (en) 2023-09-14

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